Randomized within-subject trial to evaluate smokers' initial perceptions, subjective effects and nicotine delivery across six vaporized nicotine products.

BACKGROUND AND AIMS: Vaporized nicotine products (VNPs) can vary in important characteristics including size, shape, flavor and nicotine yield. We examined whether complex interactions among these characteristics could affect smokers' VNP perceptions and usage patterns. DESIGN: A within-subject randomized cross-over trial. SETTING: Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. PARTICIPANTS: Eighteen daily cigarette smokers. MEASUREMENTS: Participants attended eight weekly visits during which they sampled six different VNPs (disposable, rechargeable, eGO, mod, e-Cigar and e-Pipe) with tobacco-flavored e-liquid. Prior to device use, participants completed product-ranking questionnaires. Participants completed controlled puffing sessions during each of the six trials, after which satisfaction questionnaires were completed and blood samples were taken. FINDINGS: Initial perceptions showed that the smallest device (disposable) was ranked as safer compared with a larger device (e-Pipe) (P < 0.05). Participants rated the eGO and mod devices higher on satisfaction and enjoyment from use, taste, pleasantness, harshness ('throat hit') and speed of effect, but lower on perceived health risk and embarrassment from use (P < 0.05). All devices had a lower Cmax than the combustible cigarette (P < 0.05), but there were differences among devices (P < 0.05). The mod, e-Pipe and eGO provided the highest amount of perceived smoking urge relief, and this correlated strongly with Cmax across all devices (R2  = 0.8614, P = 0.007). The perceived speed of urge relief was not correlated with Tmax (R2  = 0.0035, P = 0.911) CONCLUSIONS: Daily cigarette smokers testing six types of vaporized nicotine products (VNPs) reported that they varied in taste, amount of withdrawal relief, harshness, embarrassment from use, perceived health risk and subjective and objective nicotine delivery. The eGO and mod models have properties that may make them most effective for cigarette substitution among smokers who intend to switch to a VNP.

Emissions from Electronic Cigarettes: Assessing Vapers' Intake of Toxic Compounds, Secondhand Exposures, and the Associated Health Impacts.

E-cigarettes likely represent a lower risk to health than traditional combustion cigarettes, but they are not innocuous. Recently reported emission rates of potentially harmful compounds were used to assess intake and predict health impacts for vapers and bystanders exposed passively. Vapers' toxicant intake was calculated for scenarios in which different e-liquids were used with various vaporizers, battery power settings and vaping regimes. For a high rate of 250 puff day-1 using a typical vaping regime and popular tank devices with battery voltages from 3.8 to 4.8 V, users were predicted to inhale formaldehyde (up to 49 mg day-1), acrolein (up to 10 mg day-1) and diacetyl (up to 0.5 mg day-1), at levels that exceeded U.S. occupational limits. Formaldehyde intake from 100 daily puffs was higher than the amount inhaled by a smoker consuming 10 conventional cigarettes per day. Secondhand exposures were predicted for two typical indoor scenarios: a home and a bar. Contributions from vaping to air pollutant concentrations in the home did not exceed the California OEHHA 8-h reference exposure levels (RELs), except when a high emitting device was used at 4.8 V. In that extreme scenario, the contributions from vaping amounted to as much as 12 µg m-3 formaldehyde and 2.6 µg m-3 acrolein. Pollutant concentrations in bars were modeled using indoor volumes, air exchange rates and the number of hourly users reported in the literature for U.S. bars in which smoking was allowed. Predicted contributions to indoor air levels were higher than those in the residential scenario. Formaldehyde (on average 135 µg m-3) and acrolein (28 µg m-3) exceeded the acute 1-h exposure REL for the highest emitting vaporizer/voltage combination. Predictions for these compounds also exceeded the 8-h REL in several bars when less intense vaping conditions were considered. Benzene concentrations in a few bars approached the 8-h REL, and diacetyl levels were close to the lower limit for occupational exposures. The integrated health damage from passive vaping was derived by computing disability-adjusted life years (DALYs) lost due to exposure to secondhand vapor. Acrolein was the dominant contributor to the aggregate harm. DALYs for the various device/voltage combinations were lower than-or comparable to-those estimated for exposures to secondhand and thirdhand tobacco smoke.

Impact of smoking on cardiovascular events in patients with coronary disease receiving contemporary medical therapy (from the Treating to New Targets [TNT] and the Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] trials).

To define the incremental risk of cigarette smoking in patients with coronary disease receiving contemporary medical therapy, we performed a post hoc analysis of 18,885 patients by combining data from the Treating to New Targets (TNT) and the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trials. These studies compared high-dose treatment (atorvastatin 80 mg/day) to moderate-dose treatment (atorvastatin 10 mg/day in TNT and simvastatin 20 to 40 mg/day in IDEAL) in patients with established coronary heart disease. The primary end point of this pooled analysis was major cardiovascular events, a composite of cardiac death, myocardial infarction, stroke, or resuscitated cardiac arrest. At baseline 4,196 patients had never smoked, 11,513 were ex-smokers, and 3,176 were current smokers. The adjusted hazard ratio for current smokers compared to never smokers was 1.68 (95% confidence interval 1.46 to 1.94) and that for current smokers compared to ex-smokers was 1.57 (95% confidence interval 1.41 to 1.76). Event rates for current smokers compared to ex-smokers were similarly increased in each treatment group. The difference in absolute event rates between current and ex-smokers in this pooled analysis was 4.5%, which is >2 times as large as the decrease in absolute event rates between high-dose and moderate-dose statin therapy found in the IDEAL (1.7%) and TNT (2.2%) trials, respectively. In conclusion, in patients with coronary disease receiving modern medical therapy, smoking cessation is of substantial benefit with a number needed to treat of 22 to prevent a major cardiovascular event over 5 years. Smoking cessation deserves greater emphasis in secondary prevention.

Chinese "herbal" cigarettes are as carcinogenic and addictive as regular cigarettes.

OBJECTIVE: To examine the Chinese tobacco industry's claim that herbal cigarettes are less harmful than regular cigarettes. METHODS: The study design was a cross-sectional survey. One hundred thirty-five herbal cigarette smokers and 143 regular smokers from one city in China completed a questionnaire on smoking behavior and provided a urine sample. The main outcome measures were cotinine and trans-3'-hydroxycotinine in all samples, and polycyclic aromatic hydrocarbon metabolites (PAH; 1-hydroxypyrene, naphthols, hydroxyfluorenes, and hydroxyphnanthrenes) and the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-butanol (NNAL) and NNAL-glucuronide in randomly selected 98 samples (47 from the herbal smokers' group and 51 from the regular smokers' group). Values were normalized by creatinine to correct for possible variability introduced by dilution or concentration of the urine. RESULTS: Health concern was among the main reasons that smokers switched to herbal cigarettes from regular cigarettes. Smokers reported increased consumption after switching to herbal cigarettes from regular cigarettes. For all the four markers analyzed (cotinine, trans-3'-hydroxycotinine, total NNAL, and total PAHs), we observed no significant difference in the levels (P = 0.169, P = 0.146, P = 0.171, and P = 0.554, respectively) between smokers of herbal cigarettes and smokers of regular cigarettes. Both total NNAL and total PAHs were significantly correlated with cotinine and trans-3'-hydroxycotinine (P < 0.001 for all four correlations). CONCLUSIONS: Our findings showed that herbal cigarettes did not deliver less carcinogens than regular cigarettes. The public needs to be aware of this fact, and the Chinese tobacco industry should avoid misleading the public when promoting herbal cigarettes as safer products.

Hemodynamic effects of ephedra-free weight-loss supplements in humans.

PURPOSE: Ephedra-free weight loss dietary supplements containing bitter orange (Citrus aurantium), a botanical source of the adrenergic amines synephrine and octopamine, have quickly emerged on consumer markets to replace banned ephedra products. These supplements may have some of the health risks associated with ephedra, but studies in humans are lacking. Our aim was to characterize the pharmacokinetics and cardiovascular effects of C. aurantium dietary supplements. SUBJECTS AND METHODS: Ten healthy adult nonsmokers participated in a randomized, double-blind, placebo-controlled, three-arm crossover study. Single doses of C. aurantium (Advantra Z) containing 46.9 mg synephrine, Xenadrine EFX, a multi-component formulation containing 5.5 mg synephrine, and placebo were administered with a one-week washout. RESULTS: Compared with placebo, Xenadrine EFX but not Advantra Z increased systolic and diastolic blood pressure with peak changes from baseline at 2 hours of 9.6 +/- 6.2 mm Hg systolic (P = 0.047), and 9.1 +/- 7.8 mm Hg diastolic (P = 0.002). Heart rate was increased from baseline at 6 hours compared with placebo (16.7 beats per minute with Xenadrine EFX, P = 0.011; 11.4 beats per minute with Advantra Z, P = 0.031). Dose-adjusted synephrine pharmacokinetics were similar between treatments with t(max) = 90 min, t(1/2) = 3.0 hours, V/F = 16347 L, and CL/F = 88.9 L/min for Xenadrine EFX. CONCLUSION: Ephedra-free weight loss supplements have significant cardiovascular stimulant actions, similar to ephedra. These effects are not likely caused by C. aurantium alone, because an eightfold higher dose of synephrine (Advantra Z) had no effect on blood pressure, but may be attributable to caffeine and other stimulants in the multi-component formulation.

Short-term metabolic and hemodynamic effects of ephedra and guarana combinations.

OBJECTIVE: Serious adverse health events have been reported with the use of dietary supplements containing ephedra and guarana. We sought to determine whether repeated dosing and multi-ingredient formulations contribute to the adverse effects of these supplements. METHODS: In this study, 16 healthy adults (8 women) took 2 doses each of ephedra-guarana alone, Xenadrine RFA, a multicomponent dietary supplement containing 25 mg ephedra alkaloids and 200 mg caffeine, or placebo 5 hours apart in a randomized, double-blind, 3-arm crossover study. RESULTS: Peak plasma ephedrine levels averaged 130 to 140 ng/mL. Compared with placebo, Xenadrine and ephedra-guarana significantly increased heart rate (maximum increase, 9.4 +/- 8.6 beats/min; P = .002), blood pressure (maximum increase in systolic and diastolic pressure, 11.5 +/- 10.7 mm Hg and 7.3 +/- 7.4 mm Hg, respectively; P = .015), postprandial glucose concentration (maximum change, 41.0 +/- 18.8 mg/dL; P < .0001), and insulin concentration (maximum change, 41.2 +/- 47.8 microIU/mL; P = .005). Serum potassium concentrations were significantly decreased by both treatments. Hemodynamic and metabolic changes were observed after both the first and second doses. However, plasma free fatty acid concentrations increased after the first dose only. Xenadrine RFA produced higher increases in glucose concentration than ephedra-guarana, but no other pharmacodynamic differences between the treatments were found. CONCLUSIONS: Consumption of 2 doses of ephedra and guarana supplements, per supplement label recommendations, results in persistent increases in heart rate and blood pressure and unfavorable actions on glucose and potassium homeostasis. Such effects could be detrimental in persons with hypertension, atherosclerosis, or glucose intolerance, conditions that are strongly associated with obesity.

Caffeine-herbal ephedra combination increases resting energy expenditure, heart rate and blood pressure.

1. The purpose of the present study was to determine whether the consumption of an acute dose of caffeine and Ma Huang increases resting energy expenditure (REE), heart rate (HR) and blood pressure (BP) over a 3 h period. 2. A randomized, double-blind cross-over study was performed evaluating the acute effects of caffeine (150 mg)/herbal ephedra (Ma Huang; 20 mg ephedra alkaloids) versus a placebo. A total of eight healthy subjects (four males and four females) with a mean (+/-SD) age of 23.4+/-0.8 years (mean ages for males and females: 25.3+/-0.7 and 22.0+/-0.7 years, respectively) and 22.5+/-3.1% body fat (15.7+/-1.2 and 27.6+/-3.5% body fat for males and females, respectively) were recruited to the study. Participants were moderate caffeine users (approximately 150-300 mg/day). 3. Subjects reported to the laboratory following a 12 h fast and 48 h of a caffeine-free diet. Resting energy expenditure was measured prior to supplementation and for 15 min every 30 min for 3 h following supplementation. Heart rate and BP were obtained every 15 min. Blood samples were obtained every 30 min following the measurement of REE and analysed for caffeine, ephedrine, free fatty acids and glucose. 4. By 3 h, HR was 22.7+/-5.5% higher (P<0.05) than baseline for the caffeine/ephedra trial compared with 8.9+/-2.2% higher for the placebo group. At 3 h, systolic BP was 9.1+/-2.2% higher (P<0.05) than baseline for the caffeine/ephedra trial compared with only 1.9+/-2.9% different from baseline for the placebo trial. There was no effect of the caffeine/ephedra combination on diastolic BP. Resting energy expenditure during the last 30 min was 4.5+/-2.5% higher in the placebo trial and 10.7+/-2.5% higher (P<0.05) in the caffeine/ephedra trial; REE was 8.5 +/- 2.0% higher (P<0.05) in the caffeine/ephedra trial compared with the placebo trial. Free fatty acids increased over time in the placebo and caffeine/ephedra trials (from 0.5+/-0.05 to 0.63+/-0.05 mEq/L and from 0.48+/-0.06L to 0.8+/-0.05 mEq/L, respectively). 5. Caffeine and herbal ephedra, at doses of 150 mg and 20 mg (ephedrine), respectively, result in a significant elevation in REE, HR and BP. Although significant, the increase in energy expenditure is negligible in terms of weight loss.

Concentrations of ephedra alkaloids and caffeine in commercial dietary supplements.

Dietary supplements that contain Ma Huang (ephedra alkaloids) and guarana (caffeine) are widely marketed and used in the U.S. for weight loss and athletic performance enhancement, despite a lack of adequate research on the pharmacology of these botanical stimulants. We developed and applied a novel liquid chromatography-tandem mass spectrometry (LC-MS-MS) method to quantitate the various ephedra alkaloids found in dietary supplements that contain Ephedra species. The quantities of ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, methylephedine, methylpseudoephedrine, and caffeine were determined for 35 commercial dietary supplements and compared with the amounts listed on the product labels. The total ephedra alkaloid content ranged from 5.97 mg to 29.3 mg per serving. Two supplement brands did not list the quantity of ephedra alkaloids on the label, and four did not list the amount of caffeine per serving. Of the products tested, 31% contained > 110% of the total ephedra alkaloids listed on the label, and 6% of the supplements contained < 90% of the listed amount. For caffeine, 86% of the product lots that listed the caffeine amount contained less than 90% of the labeled quantity. No products contained > 110% of the declared caffeine content. The total ephedra alkaloid content varied significantly from lot to lot in 5 of 9 products. Three product brands contained proportions of alkaloids that exceeded amounts reported for E. sinica, including one that was 98% ephedrine, one that had 10% norpseudoephedrine, and one that contained an average of 13% methylephedrine. We conclude that product inconsistency is common among some commercially available dietary supplements that contain ephedra alkaloids and caffeine.

Determination of ephedra alkaloid and caffeine concentrations in dietary supplements and biological fluids.

Dietary supplements containing botanical forms of caffeine and ephedra alkaloids have been widely promoted and used in the U.S. for weight loss and athletic enhancement despite a lack of adequate research on the pharmacology of these botanical stimulants. In order to analyze dietary supplements and perform human pharmacokinetic studies, an analytical approach with good precision and accuracy was needed with sufficient sensitivity to detect very low levels of ephedra alkaloids. A liquid chromatography-atmospheric pressure chemical ionization (APCI) tandem mass spectrometry (LC-MS-MS) method was developed for quantitating the various ephedrine-group alkaloids found in dietary supplements that contain Ephedra species, and in plasma and urine of persons consuming these supplements. Using this method, low nanogram-per-milliliter concentrations of ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, methylephedrine, methylpseudoephedrine, and caffeine can be quantitated in a 12-min LC-MS-MS run.

Influence of menthol on caffeine disposition and pharmacodynamics in healthy female volunteers.

OBJECTIVES: The present study was undertaken to determine whether a single oral dose of menthol affects the metabolism of caffeine, a cytochrome P(450) 1A2 (CYP1A2) substrate, and pharmacological responses to caffeine in people. METHODS: Eleven healthy female subjects participated in a randomized, double-blind, two-way crossover study, comparing the kinetics and effects of a single oral dose of caffeine (200 mg) in coffee taken together with a single oral dose of menthol (100 mg) or placebo capsules. Serum caffeine concentrations and cardiovascular and subjective parameters were measured throughout the study. RESULTS: Co-administration of menthol resulted in an increase of caffeine t(max) values from 43.6+/-20.6 min (mean+/-SD) to 76.4+/-28.0 min ( P<0.05). The C(max) values of caffeine were lower in the menthol phase than in the placebo phase, but this effect was not statistically significant ( P=0.06). (AUC)(0-24), (AUC)(0- infinity ), terminal half-life and oral clearance were not affected by menthol. Only nine subjects' cardiovascular data were included in the analysis because of technical problems during the measurements. After caffeine, heart rate decreased in both treatment phases. The maximum decrease in heart rate was less in the menthol phase (-8.9+/-3.9 beats/min) than in the placebo phase (-13.1+/-2.1 beats/min) ( P=0.024). There were no statistically significant differences in systolic and diastolic blood pressures between the two treatments. CONCLUSIONS: We conclude that a single oral dose of pure menthol (100 mg) delays caffeine absorption and blunts the heart-rate slowing effect of caffeine, but does not affect caffeine metabolism. The possibility that menthol slows the absorption of other drugs should be considered.

Vitamin C supplementation decreases oxidative stress biomarker f2-isoprostanes in plasma of nonsmokers exposed to environmental tobacco smoke.

Exposure to environmental tobacco smoke (ETS) has been linked to increased risk of lung cancer and cardiovascular diseases in nonsmokers. Current research suggests that some of these diseases are associated with elevated oxidative stress. We investigated the effect of antioxidant (AO) intervention on the lipid peroxidation biomarker F2-isoprostanes (F2-IsoPs), an index of oxidative stress, in plasma of nonsmokers exposed to ETS (passive smokers). We measured free F2-IsoP concentrations in plasma of 67 passive smokers at baseline and after 2 mo of daily intervention with AOs or placebo. The study subjects (47 females, 20 males; mean age 46 +/-15) were randomized into one of three treatment groups: vitamin C, "mixture" (vitamin C, vitamin E, and a-lipoic-acid), and placebo. Investigated confounders included plasma baseline AO levels, lipid and total cholesterol profiles, transferrin saturation, and C-reactive protein. Plasma F2IsoP concentrations of subjects in the vitamin C and mixture groups decreased significantly by 17.2 pmol/l (P = 0.0105) and 19.2 pmol/l (P = 0.0083) when compared with the placebo group (11.4% and 12.7%, respectively). Daily AO supplementation (especially with vitamin C) decreases this oxidative stress biomarker in passive smokers. This finding might be of importance for the prevention of ETS-associated adverse health effects in nonsmokers.