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The heating of the fluids used in electronic cigarettes (\"e-cigarettes\") used to create \"vaping\" aerosols is capable of causing a wide range of degradation reaction products. We investigated formation of benzene (an important human carcinogen) from e-cigarette fluids containing propylene glycol (PG), glycerol (GL), benzoic acid, the flavor chemical benzaldehyde, and nicotine. Three e-cigarette devices were used: the JUULTM \"pod\" system (provides no user accessible settings other than flavor cartridge choice), and two refill tank systems that allowed a range of user accessible power settings. Benzene in the e-cigarette aerosols was determined by gas chromatography/mass spectrometry. Benzene formation was ND (not detected) in the JUUL system. In the two tank systems benzene was found to form from propylene glycol (PG) and glycerol (GL), and from the additives benzoic acid and benzaldehyde, especially at high power settings. With 50:50 PG+GL, for tank device 1 at 6W and 13W, the formed benzene concentrations were 1.9 and 750 μg/m3. For tank device 2, at 6W and 25W, the formed concentrations were ND and 1.8 μg/m3. With benzoic acid and benzaldehyde at ~10 mg/mL, for tank device 1, values at 13W were as high as 5000 μg/m3. For tank device 2 at 25W, all values were ≤~100 μg/m3. These values may be compared with what can be expected in a conventional (tobacco) cigarette, namely 200,000 μg/m3. Thus, the risks from benzene will be lower from e-cigarettes than from conventional cigarettes. However, ambient benzene air concentrations in the U.S. have typically been 1 μg/m3, so that benzene has been named the largest single known cancer-risk air toxic in the U.S. For non-smokers, chronically repeated exposure to benzene from e-cigarettes at levels such as 100 or higher μg/m3 will not be of negligible risk.

Quinoline-based scaffolds have been the mainstay of antimalarial drugs, including many artemisinin combination therapies (ACTs), over the history of modern drug development. Although much progress has been made in the search for novel antimalarial scaffolds, it may be that quinolines will remain useful, especially if very potent compounds from this class are discovered. We report here the results of a structure-activity relationship (SAR) study assessing potential unsymmetrical bisquinoline antiplasmodial drug candidates using in vitro activity against intact parasites in cell culture. Many unsymmetrical bisquinolines were found to be highly potent against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum parasites. Further work to develop such compounds could focus on minimizing toxicities in order to find suitable candidates for clinical evaluation.

Knowledge of the mechanism of formation, levels and toxicological profiles of the chemical products in the aerosols (i.e., vapor plus particulate phases) of e-cigarettes is needed in order to better inform basic research as well as the general public, regulators, and industry. To date, studies of e-cigarette emissions have mainly focused on chromatographic techniques for quantifying and comparing the levels of selected e-cigarette aerosol components to those found in traditional cigarettes. E-cigarettes heat and aerosolize the solvents propylene glycol (PG) and glycerol (GLY), thereby affording unique product profiles as compared to traditional cigarettes. The chemical literature strongly suggests that there should be more compounds produced by PG and GLY than have been reported in e-cigarette aerosols to date. Herein we report an extensive investigation of the products derived from vaporizing PG and GLY under mild, single puff conditions. This has led to the discovery of several new compounds produced under vaping conditions. Prior reports on e-cigarette toxin production have emphasized temperature as the primary variable in solvent degradation. In the current study, the molecular pathways leading to enhanced PG/GLY reactivity are described, along with the most impactful chemical conditions promoting byproduct production.

IntroductionThe distribution of nicotine among its free-base (fb) and protonated forms in aerosolised nicotine affects inhalability. It has been manipulated in tobacco smoke and now in electronic cigarettes by the use of acids to de-freebase nicotine and form ‘nicotine salts’.MethodsMeasurements on electronic cigarette fluids (e-liquids) were carried out to determine (1) the fraction of nicotine in the free-base form (α fb) and (2) the levels of organic acid(s) and nicotine. Samples included JUUL ‘pods’, ‘look-a-like/knock-off’ pods and some bottled ‘nicotine salt’ and ‘non-salt’ e-liquids.Results α fb= 0.12 ±0.01 at 40°C (≈ 37°C) for 10 JUUL products, which contain benzoic acid; nicotine protonation is extensive but incomplete.DiscussionFirst-generation e-liquids have α fb ≈ 1. At cigarette-like total nicotine concentration (Nictot) values of ~60 mg/mL, e-liquid aerosol droplets with α fb≈ 1 are harsh upon inhalation. The design evolution for e-liquids has paralleled that for smoked tobacco, giving a ‘déjà vu’ trajectory for α fb. For 17th-century ‘air-cured’ tobacco, α fb in the smoke particles was likely ≥ 0.5. The product α fbNictot in the smoke particles was high. ‘Flue-curing’ retains higher levels of leaf sugars, which are precursors for organic acids in tobacco smoke, resulting in α fb ≈ 0.02 and lowered harshness. Some tobacco cigarette formulations/designs have been adjusted to restore some nicotine sensory ‘kick/impact’ with α fb≈ 0.1, as for Marlboro. Overall, for tobacco smoke, the de-freebasing trajectory was α fb ≥ 0.5 → ~0 →~0.1, as compared with α fb= ~1 →~0.1 for e-cigarettes. For JUUL, the result has been, perhaps, an optimised, flavoured nicotine delivery system. The design evolution for e-cigarettes has made them more effective as substitutes to get smokers off combustibles. However, this evolution has likely made e-cigarette products vastly more addictive for never-smokers.

Electronic nicotine delivery systems (ENDS) continue to rapidly evolve. Current products pose unique challenges and opportunities for researchers and regulators. This commentary aims to highlight research gaps, particularly in toxicity research, and provide guidance on priority research questions for the tobacco regulatory community. Disposable flavoured ENDS have become the most popular device class among youth and may contain higher nicotine levels than JUUL devices. They also exhibit enhanced harmful and potentially harmful constituents production, contain elevated levels of synthetic coolants and pose environmental concerns. Synthetic nicotine and flavour capsules are innovations that have recently enabled the circumvention of Food and Drug Administration oversight. Coil-less ENDS offer the promise of delivering fewer toxicants due to the absence of heating coils, but initial studies show that these products exhibit similar toxicological profiles compared with JUULs. Each of these topic areas requires further research to understand and mitigate their impact on human health, especially their risks to young users.

The electronic cigarette solvents propylene glycol and glycerol are known to produce toxic byproducts such as formaldehyde, acetaldehyde and acrolein. However, the aerosol toxin yield depends upon a variety of chemical and physical variables. The formaldehyde hemiacetals derived from these solvents were reported as major electronic cigarette aerosol components by us in 2015. In the study described herein, the formaldehyde hemiacetals were found at higher levels than those of free formaldehyde via an orthogonal sample collection protocol. In addition, the common aldehyde collection methods for electronic cigarettes, such as impingers and sorbent tubes containing DNPH, significantly underestimate the levels of formaldehyde. The reason for this is that formaldehyde hemiacetals follow other reaction pathways, such as the formation of a less reactive full cyclic acetal catalyzed by the acidity of the DNPH solution and the silica. We found that formaldehyde hemiacetals are a considerable fraction of the total formaldehyde produced in electronic cigarette that cannot be determined accurately by DNPH derivatization methods. Although the health effects of the hemiacetals are not yet known, they warrant further investigation.

To the Editor: The data presented by Jensen et al. (Jan. 22 issue) 1 in their recent letter to the Editor do not support their conclusion that e-cigarette use presents a likely risk of excessive exposure to formaldehyde. The 5-V puff topography used by Jensen et al. appears to have overheated the coil, resulting in excessive breakdown of propylene glycol to formaldehyde. This phenomenon is readily detected by the consumer by virtue of an exceedingly unpleasant burning taste, commonly referred to as a “dry puff.” It has been described in detail in the literature. 2 , 3 The consumer can address this issue . . .

IntroductionThere is an urgent need to develop new drugs to treat malaria due to increasing resistance to first-line therapeutics targeting the causative organism, Plasmodium falciparum (P. falciparum). One drug candidate is DM1157, a small molecule that inhibits the formation of hemozoin, which protects P. falciparum from heme toxicity. We describe a first-in-human, phase 1 trial of DM1157 in healthy adult volunteers that was halted early because of significant toxicity.MethodsAdverse events were summarized using descriptive statistics. We used pharmacokinetic modeling to quantitatively assess whether the DM1157 exposure needed for P. falciparum inhibition was achievable at safe doses.ResultsWe found that there was no dose where both the safety and efficacy target were simultaneously achieved; conversely, the model predicted that 27 mg was the highest dosage at which patients would consistently maintain safe exposure with multiple dosing. By pre-defining dose escalation stopping rules and conducting an interim pharmacokinetic/pharmacodynamic analysis, we determined that the study would be unable to safely achieve a dosage needed to observe an anti-malarial effect, thereby providing strong rationale to halt the study.ConclusionThis study provides an important example of the risks and challenges of conducting early phase research as well as the role of modeling and simulation to optimize participant safety (ClinicalTrials.gov, NCT03490162).

Background Chloroquine (CQ) resistance in P. falciparum is strongly linked to mutations in the gene pfcrt that gives rise to the protein, PfCRT (P. falciparum chloroquine resistance transporter), located in the parasite's digestive vacuole (DV) membrane [1]. In CQ resistant (CQR) strains, accumulation of CQ is reduced in the DV due to increased efflux [2], relative to CQ sensitive (CQS) malaria.