Philip Morris USA

It has been reported that nicotine affects brain dopamine homeostasis. By binding to nicotinic acetylcholine receptors, including those expressed by dopaminergic neurons of the ventral tegmental area, nicotine stimulates dopamine release and signaling. Dopamine is taken up from the synaptic cleft by the dopamine transporter (DAT) into presynaptic neurons, where it is degraded by monoamine oxidase (MAO). Besides nicotine, other tobacco compounds play a role in dopamine modulation. To better understand the biological effects of nicotine and other tobacco compounds on dopamine regulation, we selected a group of tobacco compounds based on their potential affinity to bind human MAO-A and MAO-B enzymes using an in silico approach. Subsequently, we tested the putative compounds in an enzymatic assay to verify their ability to inhibit human MAO-A or MAO-B. The positive hits were harman, norharman, harmaline, and 1-ethyl-β-carboline. While harman and norharman have been extensively studied, both harmaline and 1-ethyl-β-carboline have not been described in the context of tobacco and MAO inhibition before. We investigated DAT activity in an overexpressing cell line and dopamine release and uptake in rat striatal synaptosomes. We clearly demonstrate that tested MAO-A inhibitors (MAO-AIs) significantly attenuated human DAT activity and consequent dopamine uptake, establishing a functional connection between MAOIs and dopamine uptake via DAT. Interestingly, the tested MAO-AIs elicited pronounced dopamine release in crude synaptosomal preparations. In summary, this in vitro study demonstrates that tested MAO-AIs found in cigarette smoke not only reduce MAO activity but also strongly impact dopamine homeostatic mechanisms via DAT. Further in vivo investigations would advance our understanding of the underlying mechanisms of dopamine regulation and homeostasis.

Smoking is a known risk factor for cardiovascular diseases (CVD). Despite widespread knowledge of the health risks of combustible cigarettes (CIG), many smokers continue to smoke. There have been efforts to provide alternatives, such as heated tobacco products (HTP), that may be less harmful than CIG. To evaluate the impact of switching from CIG to HTP on the time to first subsequent major adverse cardiovascular event (MACE) compared with continued CIG smoking. This retrospective cohort study will use health data from the Tokushukai Medical Database and tobacco exposure data from questionnaires and consumer databases in Japan. The study will include patients with a first cardiovascular event of non-fatal myocardial infarction (MI), unstable angina, or urgent coronary revascularization between May 2016 and December 2020 (Index Event); patients will be observed until March 2025. The primary exposure of interest is HTP use, while the primary comparator is continued CIG smoking pre- and post-index. The primary outcome is first post-index MACE (a composite outcome of any of the following: non-fatal MI, non-fatal stroke, hospitalization for angina, hospitalization for heart failure, urgent revascularization for angina, or all-cause mortality). After accounting for potential confounding factors with a propensity score weighting method, weighted log-rank tests and a weighted non-proportional Cox model will be used to compare the primary outcome between the exposure groups. Dual use of CIG and HTP, quitting CIG, and never smoking will also be analyzed as ancillary exposure groups to address secondary objectives. The study described in this protocol intends to assess whether there is a longer time to first MACE in HTP users as compared to CIG smokers. This protocol describes a large-scale study that intends to identify patients with CVD from a nationally representative healthcare database and utilizes multiple data sources to evaluate their history of tobacco product usage. This will be the first study to assess the effect of HTP use on CVD outcomes by sex. Given the limited evidence on the health impacts of HTP in relation to CVD, the results of this study will provide insights into the effect of switching to HTP use compared to continued CIG smoking in patients with a prior cardiovascular event.

We investigated the applicability of proton transfer reaction-time-of-flight mass spectrometry (PTR-TOF-MS) for quantitative analysis of mixtures comprising glycerin, acetol, glycidol, acetaldehyde, acetone, and propylene glycol. While PTR-TOF-MS offers real-time simultaneous determination, the method selectivity is limited when analyzing compounds with identical elemental compositions or when labile compounds present in the mixture produce fragments that generate overlapping ions with other matrix components. In this study, we observed significant fragmentation of glycerin, acetol, glycidol, and propylene glycol during protonation via hydronium ions (H3O+). Nevertheless, specific ions generated by glycerin (m/z 93.055) and propylene glycol (m/z 77.060) enabled their selective detection. To thoroughly investigate the selectivity of the method, various mixtures containing both isotope-labeled and unlabeled compounds were utilized. The experimental findings demonstrated that when samples contained high levels of glycerin, it was not feasible to perform time-resolved analysis in H3O+ mode for acetaldehyde, acetol, and glycidol. To overcome the observed selectivity limitations associated with the H3O+ reagent ions, alternative ionization modes were investigated. The ammonium ion mode proved appropriate for analyzing propylene glycol (m/z 94.086) and acetone (m/z 76.076) mixtures. Concerning the nitric oxide mode, specific m/z were identified for acetaldehyde (m/z 43.018), acetone (m/z 88.039), glycidol (m/z 73.028), and propylene glycol (m/z 75.044). It was concluded that considering the presence of multiple product ions and the potential influence of other compounds, it is crucial to conduct a thorough selectivity assessment when employing PTR-TOF-MS as the sole method for analyzing compounds in complex matrices of unknown composition.